Paget’s disease of bone (PDB) is the second most prevalent metabolic bone disorder worldwide, with a prevalence rate of 1.5%–8.3%. It is characterized by localized areas of accelerated, disorganized, and excessive bone production and turnover. Typically, PDB develops in the later stages of life, particularly in the late 50s, and affects men more frequently than women. PDB is a complex disease influenced by both genetic and environmental factors. PDB has a complex genetic basis involving multiple genes, with SQSTM1 being the gene most frequently associated with its development. Mutations affecting the UBA domain of SQSTM1 have been detected in both familial and sporadic PDB cases, and these mutations are often associated with severe clinical expression. Germline mutations in other genes such as TNFRSF11A, ZNF687 and PFN1, have also been associated with the development of the disease. Genetic association studies have also uncovered several PDB predisposing risk genes contributing to the disease pathology and severity. Epigenetic modifications of genes involved in bone remodelling and regulation, including RANKL, OPG, HDAC2, DNMT1, and SQSTM1, have been implicated in the development and progression of Paget’s disease of bone, providing insight into the molecular basis of the disease and potential targets for therapeutic intervention. Although PDB has a tendency to cluster within families, the variable severity of the disease across family members, coupled with decreasing incidence rates, indicates that environmental factors may also play a role in the pathophysiology of PDB. The precise nature of these environmental triggers and how they interact with genetic determinants remain poorly understood. Fortunately, majority of PDB patients can achieve long-term remission with an intravenous infusion of aminobisphosphonates, such as zoledronic acid. In this review, we discuss aspects like clinical characteristics, genetic foundation, and latest updates in PDB research.

中文翻译：

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佩吉特病：流行病学、病因学、遗传学和治疗综述

佩吉特骨病（PDB）是世界范围内第二常见的代谢性骨病，患病率为 1.5%–8.3%。其特点是局部区域骨生成和周转加速、无组织和过度。通常，PDB 发生在生命的后期，尤其是 50 多岁，并且男性比女性更容易受到影响。PDB是一种受遗传和环境因素影响的复杂疾病。PDB 具有涉及多个基因的复杂遗传基础，其中 SQSTM1 是与其发育最常相关的基因。在家族性和散发性 PDB 病例中均检测到影响 SQSTM1 UBA 结构域的突变，这些突变通常与严重的临床表达相关。其他基因（例如 TNFRSF11A、ZNF687 和 PFN1）的种系突变也与该疾病的发生有关。遗传关联研究还发现了一些导致疾病病理学和严重程度的 PDB 易感风险基因。参与骨重塑和调节的基因（包括 RANKL、OPG、HDAC2、DNMT1 和 SQSTM1）的表观遗传修饰与佩吉特骨病的发生和进展有关，为了解该疾病的分子基础和潜在靶点提供了见解。治疗干预。尽管PDB有在家庭内聚集的趋势，但家庭成员之间疾病的严重程度不同，加上发病率下降，表明环境因素也可能在PDB的病理生理学中发挥作用。这些环境触发因素的确切性质以及它们如何与遗传决定因素相互作用仍然知之甚少。幸运的是，大多数 PDB 患者可以通过静脉输注氨基二膦酸盐（例如唑来膦酸）实现长期缓解。在这篇综述中，我们讨论了 PDB 研究的临床特征、遗传基础和最新更新等方面。